09-21 nanoparticle-mediated RNA delivery_cropped

[Image above] A schematic illustration of bioceramic oxide (e.g., ceria, silica) and metal (gold, silver) nanoparticles delivering therapeutic microRNA to a cutaneous wound. Credit: Ryan Dickerson, University of Central Florida

Cerium is one element that many people may not recognize, but in its oxide form, this compound is gaining a lot of attention in the medical field.

Cerium is the most abundant rare-earth metal found in the Earth’s crust. Traditionally, powdered cerium oxide is used as an abrasive to grind or polish hard materials such as glass. In recent years, however, cerium oxide also gained attention in biological fields when it was discovered that nanoparticles of this material possess multi-enzyme-like properties, including the ability to act as both an oxidation catalyst and reduction catalyst.

Sudipta Seal is one researcher actively involved in exploring the potential of cerium oxide nanoparticles (nanoceria) in medicine. Seal is Pegasus Professor, University Distinguished Professor, and chair of the University of Central Florida’s Department of Materials Science and Engineering.

His research on nanoceria includes using it to reduce damage from radiation exposure and to develop a rapid detector of dopamine for point-of-care diagnostics. Last month, Seal and his colleagues published two papers that explore some other applications of nanoceria in medicine—wound healing and surface disinfectant.

Healing wounds through nanoparticle-mediated RNA delivery

In the first paper published August 8, Seal and his colleagues at UCF and Kenneth W. Liechty at the University of Colorado Denver School of Medicine reviewed recent work being done on nanoparticle-mediated RNA delivery for wound healing.

Ribonucleic acid, or RNA, is a polymeric molecule essential in various biological roles in the coding, decoding, regulation, and expression of genes. Because many human diseases are influenced by genetic factors, researchers have become very interested in developing RNA-based therapies to regulate disease-causing genes and their variants.

A handful of RNA-based products are approved for use in the clinic, including the COVID-19 vaccine developed by Pfizer-BioNTech. Most of these products are based on noncoding RNA, which mean the molecules do not get translated into a functional protein. (The COVID-19 vaccines by Pfizer-BioNTech and Moderna are based on messenger RNA, however, meaning the molecules are translated into protein.)

microRNA (miRNA) is a class of noncoding RNA that has received a lot of attention since its discovery in the early 1990s. These small, single-stranded RNA molecules primarily regulate post-transcriptional stages of gene expression, and almost every biological process is controlled by miRNA-mediated mechanisms.

To date, no miRNA-based drug has been approved for clinical use due to challenges with effectively delivering the molecule to the treatment site. However, multiple clinical trials are currently ongoing, and researchers are hopeful that some miRNA-based therapies will be approved for clinical use soon.

(Learn more about the use of miRNA to treat wounds in the new October/November issue of the ACerS Bulletin.)

Nanoparticle-based delivery systems are one method being investigating to effectively deliver miRNA molecules to the treatment site. Not only do nanoparticles move more freely in the human body compared to bigger materials, but researchers also showed they can stay in the blood circulatory system for a prolonged period, enabling release of drugs per a specified dose.

In the review paper, Seal and his colleagues included a section on the use of cerium oxide nanoparticles for nanoparticle-mediated RNA delivery. They described several successful studies, including one from their group in 2019 that used cerium oxide nanoparticles to deliver miRNA to treat diabetic wounds.

They also discussed studies using gold, calcium phosphate, silica, and mesoporous silica nanoparticles. But overall, “Among the inorganic nanoparticles, [cerium oxide] seems to be the most promising nanoparticle for miRNA delivery as it is an antioxidant and can deliver key miRNA molecules that can affect the inflammatory phase of wound healing,” they conclude.

The paper, published in WIREs Nanomedicine and Nanobiotechnology, is “Nanoparticle mediated RNA delivery for wound healing” (DOI: 10.1002/wnan.1741).

Metal-mediated nanoscale cerium oxide demonstrates potential as surface disinfectant

In the second paper published August 26, Seal and his colleagues at UCF and Kismet Technologies explored the potential of two distinct silver-modified nanoscale cerium oxide formulations as a surface disinfectant.

During the past year, the evolving SARS-CoV2 pandemic heightened public awareness of the high transmissibility and infectivity of respiratory viruses. As such, there was a surge in funding for fundamental and applied virus-related research, including development of improved surface disinfectants.

In a UCF press release, Christina Drake, founder of Kismet Technologies and co-author on the recent paper, says her initial thought was to explore developing a fast-acting disinfectant. However, after speaking with doctors and dentists to find out what they wanted in a disinfectant, “What mattered the most to them was something long-lasting that would continue to disinfect high-touch areas like doorhandles and floors long after application,” she says.

Drake partnered with Seal and Griff Parks, associate dean of research and director of the UCF Burnett School of Biomedical Sciences, to look into developing a long-lasting disinfectant. They chose silver-modified nanoscale cerium oxide for several reasons.

One, metal and metal oxide nanomaterials are frequently studied for various antibacterial and antiviral applications due to their broad-spectrum antibacterial activity and antiviral efficacy, as well as being less susceptible to deactivation through physical and chemical conditions. Silver in particular is a common choice because of its strong antimicrobial activity. Two, cerium oxide nanoparticles are desirable for the multi-enzyme-like properties discussed above.

The researchers fabricated two distinct silver-modified nanoscale cerium oxide formulations using different chemical reactions specific to aqueous silver. They then tested the nanoparticles’ ability to inactivate pathogens by adding the nanoparticles to solutions containing viruses that can cause the common cold: the seasonal coronavirus OC43 (an enveloped RNA virus) or rhinovirus 14 (a nonenveloped RNA virus).

The researchers found that the first silver formulation (AgCNP1) was highly effective at inactivating coronavirus OC43, while the second silver formulation (AgCNP2) had a modest capacity for inactivation. On the other hand, AgCNP2 proved highly effective at inactivating rhinovirus 14, while AgCNP1 was less so. In comparison, related nanoceria formulations that did not contain silver had little effect on the viruses.

In the conclusion, the researchers say further biochemical and structural studies are needed to determine the factors that dictate the ability of silver-modified nanoscale cerium oxide to inactivate an enveloped versus nonenveloped RNA virus. However, based on the results in this study, they propose two different mechanisms for their nanoparticles.

  • In the case of AgCNP1, the dominant physical interaction with the OC43 envelope appears to disrupt the lipid bilayer (observable in an electrochemical experiment as changes to resistive/capacitive values).
  • In the case of AgCNP2, the chemical reactivity with the protein shell of rhinovirus 14 inactivates the pathogen by denaturing the proteins involved in receptor binding (as observed experimentally as evolution of the equivalent circuit diagram from in situ measurements).

In the press release, Parks says the nanoparticles also proved effective against a wide range of other viruses with different structures and complexities. “We are hopeful that with this amazing range of killing capacity, this disinfectant will also be a highly effective tool against other new emerging viruses,” he says.

The paper, published in ACS Nano, is “Metal-mediated nanoscale cerium oxide inactivates human coronavirus and rhinovirus by surface disruption” (DOI: 10.1021/acsnano.1c04142).